Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States

BACKGROUND: In the United States, major depressive disorder (MDD) is one of the most prevalent mental health disorders. Treatment guidelines for MDD recommend pharmacologic and nonpharmacologic therapies tailored to the patient’s disease severity, level of function, and comorbid health conditions. While previous studies examined real-world pharmacologic treatment patterns and costs among patients with MDD, few have examined the use of nonpharmacologic treatments and their association with health care resource utilization (HCRU) and cost. OBJECTIVE: To describe prevalence and associations between patient/provider characteristics and treatment modality and characterize HCRU and cost by treatment modality for patients with newly diagnosed MDD. METHODS: Commercially insured US patients, aged 18-62 years with newly diagnosed MDD between January 1, 2017, and September 30, 2019, were retrospectively identified from the Healthcare Integrated Research Database. Eligible patients were continuously enrolled in the health plan for 1 year before and 2 years after the first MDD diagnosis (index date). Those with co-occurring schizophrenia, bipolar disorder, postpartum depression, substance use disorder, and any prior MDD treatments were excluded. Treatment modalities assessed in the 2-year post-index period included antidepressant only (Rx-only), nonpharmacologic only (non–Rx-only), both antidepressant and nonpharmacologic (combination), and no treatment. HCRU and costs were assessed in the 2-year post-index period by treatment modality. Regression models identified associations between patient/provider characteristics and treatment modality, and the relationship between treatment modality and MDD severity changes. RESULTS: In total, 12,657 patients were included (mean age: 36 years; 60% female). During follow-up, 34% of patients received Rx-only, 25% received non–Rx-only, 28% received combination, and 13% received no treatment. MDD severity at diagnosis (26% mild, 54% moderate, 20% severe) was available for 51% of patients. Post-index inpatient hospitalizations were 11% for those with Rx-only, 10% for non–Rx-only, 16% for combination, and 29% for no treatment, whereas all-cause mean monthly total costs were $792, $633, $786, and $1,292, respectively. In multinomial logistic regression, age, sex, geographic region and urbanicity of patient residence, socioeconomic status, diagnosing provider specialty, and initial diagnosis location were significantly associated (P < 0.05) with treatment modality. In multivariable logistic regression, recipients of Rx-only (odds ratio = 2.03, P < 0.01) or combination (odds ratio = 3.26, P < 0.01) had higher odds of improving MDD severity than patients who received no treatment. CONCLUSIONS: In this real-world sample of commercially insured patients, we observed variations in outcomes by treatment modality and an association between treatment modality and disease severity. Further research is needed to explore the underlying causal relationships between treatment modality and patient outcomes. Study Registration: https://doi.org/10.17605/OSF.IO/YQ6B3

Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States that combination use of psychotherapy and antidepressants produces better outcomes than either treatment on its own. 11,12 To date, few studies have examined real-world treatment patterns, health care resource utilization (HCRU), and health care costs among patients with MDD, and those that have largely focused on examining the role of antidepressant treatment without examining the role of nonpharmacologic treatment alone or in combination with antidepressant treatment. [13][14][15][16] Furthermore, prior research examining real-world outcomes often has not included information on important covariates such as those pertaining to social determinants of health and disease severity. The purpose of this study was to examine utilization of both antidepressant and nonpharmacologic treatments as well as the relationship between treatment modality and patient outcomes such as HCRU, health care costs, and disease severity.

DATA SOURCE AND STUDY DESIGN
We conducted a retrospective, observational cohort study using administrative claims from the Healthcare Integrated Research Database. This database includes medical and pharmacy claims from 14 states in the United States. 17 Member enrollment data, inpatient and outpatient medical care, and outpatient prescription drug use are tracked longitudinally for each member. Researchers accessed data in the format of a limited dataset, for which data use agreements were in place with the covered entities in adherence with the Health Insurance Portability and Accountability Act Privacy Rule, and therefore, institutional review board approval was not required. The full study protocol is available through the Real-World Evidence Registry: https://osf. io/yq6b3.

STUDY POPULATION
Patients with commercial health insurance coverage who had at least 1 inpatient or emergency department visit or at least 2 outpatient visits (at least 30 days apart but not more than 183 days apart) with a diagnosis of MDD during the patient selection period (January 1, 2017, to September 30, 2019) were included in the study. The earliest MDD diagnosis date was set as the index date. Patients included could not have any claims for MDD or MDD treatment in their history prior to their index date. Furthermore, patients could not have a diagnosis of schizophrenia, bipolar disorder, postpartum depression, substance use disorder, an intellectual disability, or a neurocognitive disorder during the study period (January 1, 2006, to September 30, 2021), Major depressive disorder (MDD) is a psychiatric condition characterized by a variety of symptoms including depressed mood, loss of pleasure or interest, sleep disturbance, significant weight loss or gain, excessive feelings of guilt or worthlessness, and suicidal ideation. 1 In the United States, MDD is one of the most prevalent mental health disorders; in 2020, 8.4% of US adults reported experiencing at least 1 major depressive episode in the previous year. 2 The estimated lifetime risk of depression in the United States is approximately 30%. 3 MDD is frequently associated with comorbid psychiatric and nonpsychiatric conditions and multiple impacts on health status including reduced quality of life. 4,5 Furthermore, MDD increases risk of death by 60%-80%, and patients with MDD are nearly 20 times as likely to die by suicide than the general population. [6][7][8] Treatment guidelines from the American Psychiatric Association and American Psychological Association recommend both pharmacologic and nonpharmacologic therapies that should be individually tailored based on disease severity, level of function, comorbid behavioral and physical health conditions, patient preference, and cost. 9,10 Recommendations for first-line pharmacologic treatment from the American Psychiatric Association include antidepressants with a specific focus on selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), mirtazapine, or bupropion, whereas the American Psychological Association specifically recommends SSRIs and SNRIs. 9,10 In terms of nonpharmacologic treatments, both guidelines recommend psychotherapy (eg, cognitive behavioral therapy) as an option for initial treatment of MDD, either alone or in combination with antidepressant medication. 9,10 Clinical studies have shown hospitalizations were 11% for those with Rx-only, 10% for non-Rx-only, 16% for combination, and 29% for no treatment, whereas all-cause mean monthly total costs were $792, $633, $786, and $1,292, respectively. In multinomial logistic regression, age, sex, geographic region and urbanicity of patient residence, socioeconomic status, diagnosing provider specialty, and initial diagnosis location were significantly associated (P < 0.05) with treatment modality. In multivariable logistic regression, recipients of Rx-only (odds ratio = 2.03, P < 0.01) or combination (odds ratio = 3.26, P < 0.01) had higher odds of improving MDD severity than patients who received no treatment.

CONCLUSIONS:
In this real-world sample of commercially insured patients, we observed variations in outcomes by treatment modality and an association between treatment modality and disease severity. Further research is needed to explore the underlying causal relationships between treatment modality and patient outcomes. Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States ie, both before and after their index date during all available data. Patients were required to be aged between 18 and 62 years on the index date (ie, patient could not be aged ≥ 65 years during follow-up to exclude transitions into Medicare insurance) and have continuous medical and pharmacy benefit enrollment during the 1-year baseline and 2-year post-index follow-up periods. Patients whose pharmacy benefit was carved out, resulting in missing cost data, were excluded. See Supplementary Tables 1-3 (available in online article) for code lists and Supplementary Figure 1 for the study design diagram.

STUDY MEASURES
Patient demographics were assessed on the index date, whereas the Quan-Charlson Comorbidity Index score, other comorbidities, and medication use (glucocorticoids, narcotic analgesics, and non-narcotic analgesics) were assessed during the baseline period. 18 Patients were linked to data from the 2017 American Community Survey 5-year estimates at the Census block group level based on their location of residence on the index date. 19 Socioeconomic status (SES) index score was calculated for each patient based on a composite of 7 variables from the American Community Survey including unemployment rate, poverty rate, median household income, median home value, rate of no high school diploma, rate of college degree, and crowding. 20 A score of 4 indicates the patient is in the top 25% of SES, and a score of 1 indicates the patient is in the bottom 25% of SES using all Census block groups in the United States.
MDD severity was assessed using International Classification of Diseases, Tenth Revision, Clinical Modification coding for severity on the medical claims and categorized as mild, moderate, severe, or in remission (Supplementary Table 1). Initial MDD severity was assessed between the index date and 30 days post-index. For those with different severity assessments during that time, patients were assigned the higher severity (eg, a patient with both a moderate and severe code would be labeled severe). Post-index severity changes were assessed between days 31 and 730 post-index among those with at least 1 claim with severity specified during that time and at least 1 claim specified at index. Patients were categorized as having no severity change, worsened severity, or improved severity by comparing the initial and last available severity assessment.
Treatment was assessed during the 2-year post-index period. Nonpharmacologic treatment in the post-index period was identified using Current Procedural Terminology codes (Supplementary Table 3). Antidepressant treatments were identified from any medical or pharmacy claims with a Healthcare Common Procedure Coding System code or Generic Product Identifier code for a treatment of interest. Antidepressants included SSRIs, SNRIs, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, serotonin modulators and stimulators, bupropion, mirtazapine, esketamine, and ketamine. Patients ended their current line of treatment when they discontinued their existing antidepressant (defined as a gap of 60 days or more between the depletion date [ie, date of last fill plus days supply on hand] and their subsequent fill), switched antidepressants, or added (or removed) an antidepressant to (or from) their initial antidepressant regimen. Restarting an antidepressant (either the same or a different antidepressant) after discontinuation, switching antidepressants, or adding (or removing) an antidepressant to (or from) the regimen prompted the start of a new line of treatment. Treatment patterns were assessed at the class-level for the 5 classes of drugs (SSRIs, SNRIs, TCAs, monoamine oxidase inhibitors, and serotonin modulators and stimulators) and the druglevel for the 4 specified drugs (bupropion, mirtazapine, esketamine, and ketamine). Changes in medications within the same class were not considered.
Patients were further categorized into 1 of 4 treatment modalities based on antidepressant and nonpharmacologic treatment utilization at any time in the post-index period: (1) those who received antidepressant treatment only (Rxonly); (2) those who received nonpharmacologic treatment only (non-Rx-only); (3) those who received both antidepressant and nonpharmacologic treatment (combination); or (4) those who received no treatment (none) during the post-index period.
All-cause HCRU and health care costs were assessed during the post-index period by treatment modality. Allcause costs were adjusted to 2021 US dollars based on the most recent medical price index information provided by the Bureau of Labor Statistics and calculated as the combined health-plan-paid, member-paid, and coordination-of-benefits (third-party payer) costs. 21

STATISTICAL ANALYSIS
Demographics, clinical characteristics, treatment patterns, HCRU, and health care costs were presented using descriptive statistics. A Sankey diagram showing the antidepressant treatment lines was created for up to 4 lines of treatment. HCRU was presented as number and percent of patients with any use during the post-index period, whereas health care costs were presented as monthly mean costs calculated by taking the sum of costs over the post-index period and dividing by the total number of months during the post-index period (ie, 2 years). Multinomial logistic regression was used to identify associations between baseline patient/provider characteristics (exposure) and treatment Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States

DEMOGRAPHICS AND BASELINE CHARACTERISTICS
In total, 12,657 patients met cohort selection criteria (Supplementary Figure 2) with a mean age of 35.6 years and 60% female. Most were diagnosed with MDD by a primary care physician (PCP) (36%) or nonphysician clinician (34%) such as a psychologist, nurse practitioner, or licensed clinical social worker (LCSW). Furthermore, most (86%) were diagnosed in an outpatient setting. Patients also had low Quan-Charlson Comorbidity Index scores (mean score: 0.18) and a low prevalence of other comorbid conditions (Table 1).

TREATMENT PATTERNS
Among all patients with MDD, 4,282 (34%) received Rx-only treatment, 3,121 (25%) received non-Rx-only treatment, 3,554 (28%) received combination treatment, and 1,700 (13%) received no treatment over 2 years of follow-up. Of the 7,836 patients who had any antidepressant medication treatment, 54% had 1 treatment line, whereas 46% had 2 or more treatment lines during the post-index period. The most common first-line treatment was SSRI monotherapy, and this remained the most common treatment regimen throughout the first 4 lines of treatment (Supplementary Figure 3). The most common nonpharmacologic treatment was individual, family, or group psychotherapy, used by 90% (6,033/6,675) of patients with any nonpharmacologic treatment (data not shown).
In adjusted multinomial logistic regression (Figure 1; Supplementary Table 5), significant sociodemographic associations with treatment modality were identified. Older (continued on next page) Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States no treatment. Those living in the Northeast also had higher odds of receiving combination treatment over no treatment than those living in the South. Those living in the Northeast and West had lower odds of receiving Rx-only treatment vs no treatment than those living in the South. Treatment modality was also associated with rurality; those living in rural locations were less likely to receive non-Rx-only vs no treatment than those living in urban locations and more likely to receive Rx-only vs no treatment, but there was no statistical difference between receiving combination vs no treatment. Those with higher SES (quartile of 4 or 3 vs 1) had higher odds of non-Rx-only treatment vs no treatment and combination vs no treatment.
Additionally, the association between diagnosing provider specialty and treatment modality varied ( Figure 1; Supplementary Table 5). Those diagnosed by a psychiatrist, emergency medicine physician, or nonphysician clinician had higher odds of receiving non-Rx-only treatment vs no treatment compared with those diagnosed by a PCP. Similarly, those diagnosed by a psychiatrist or nonphysician clinician also had higher odds of receiving combination treatment vs no treatment than those diagnosed by a PCP. Conversely, those diagnosed by an emergency medicine physician or nonphysician clinician had lower odds of receiving Rx-only treatment vs no treatment than those diagnosed by a PCP. Finally, location of diagnosis was associated with treatment modality; those diagnosed in an outpatient setting were more likely to receive non-Rx-only, Rx-only, or combination treatments vs no treatment than those diagnosed in an emergency department or inpatient setting.

MDD SEVERITY
Among the total patient population, 6,444 (51%) had MDD severity specified on their index diagnosis claim, with 26% coded as mild, 54% as moderate, and 20% as severe MDD. All patients whose MDD severity was specified on the index claim also had a specified diagnosis in the post-index period. Most (76%) patients did not change MDD severity between the index and last specified severity in the post-index, but 18% improved severity while 6% worsened severity ( Table 2).
In multivariable logistic regression examining associations with MDD severity improvement, neighborhood-level SES, diagnosing provider specialty, index severity, and post-index treatment modality were significantly associated with severity improvement (Figure 2; Supplementary  Table 6). Those who lived in neighborhoods of high SES were more likely to improve severity than those living in neighborhoods of low SES. Those diagnosed by a psychiatrist, psychologist, or LCSW all had lower odds of improving severity than those diagnosed by a PCP. Index severity was patients were less likely to receive Rx-only, non-Rx-only, or combination treatments than no treatment, and compared with male patients, female patients were more likely to receive nonpharmacologic treatment than no treatment. Compared with those living in the South, those living in the Northeast had higher odds and those in the Midwest had lower odds of receiving nonpharmacologic treatment over Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States   also associated with severity improvement, with those who had moderate MDD at index having 3.33 times the odds (95% CI = 2.66-4.18) and those who had severe MDD at index having 8.37 times the odds (95% CI = 6.51-10.77) of severity improvement in the post-index period than those who had mild MDD at index. Finally, post-index treatment modality was significantly associated with severity improvement. Those who received Rx-only were 2.03 times more likely (95% CI = 1.37-3.02) and those who had combination treatment were 3.26 times more likely to improve severity (95% CI = 2.20-4.82) compared with those who had no treatment.

HCRU AND HEALTH CARE COST
In the post-index period, those who received no treatment had the numerically highest HCRU and mean health care cost. Specifically, 29% of those who had no treatment had at least 1 inpatient hospitalization in the post-index period whereas only 11%, 10%, and 16% of those who had Rx-only, non-Rx-only, and combination treatment modalities, respectively, had at least 1 inpatient hospitalization. Prevalence of emergency department utilization in the post-index period was similarly higher among those who received no treatment; 46% of those who had no treatment had an emergency department visit, whereas 28%, 22%, and 30% of those with Rx-only, non-Rx-only, and combination treatments, respectively, had an emergency department visit. Finally, the mean monthly all-cause costs were $1,292 in the no treatment group in the post-index period, whereas costs were $792, $633, and $786 for those with Rx-only, non-Rx-only, and combination treatments, respectively (Figure 3; Supplementary Table 4).

Discussion
To our knowledge, this is one of the first studies assessing real-world treatment modalities for MDD that includes an examination of the role of both antidepressant and nonpharmacologic treatments. In this retrospective study in a US commercially insured managed care population, patients who received no treatment of MDD had the numerically highest HCRU and mean all-cause costs, whereas those who received combination treatment had the highest odds of improving their MDD severity post-index. It should be noted that these estimates reflect associations only and  further research is needed to disentangle the underlying causal pathways. For example, a patient's MDD severity may change multiple times after initial diagnosis, which may lead to changes in treatment; the reverse can also happen. Our exploratory analysis abstracted from these issues of timing and endogeneity. According to treatment guidelines, antidepressant medication and psychotherapy alone or in combination are recommended as first-line treatments for MDD. 9,10 In the United States, it is estimated that only two-thirds of adults with a major depressive episode received any treatment (either medication or psychotherapy) in 2020. 2 Our study found that 87% of patients received treatment (either antidepressant or nonpharmacologic treatment); however, our study focused on commercially insured adults diagnosed with MDD and assessed treatment over 2 years, which is likely contributing to the higher percentage compared with the national estimate. Nevertheless, 13% of patients in our sample received no treatment after their diagnosis, and this is likely an underestimate of the true prevalence of untreated depression as many individuals might be undiagnosed and would not be captured in our sample or treated for depression. 23 Stigma, antidepressant safety and effectiveness, severity of depression, patient and physician preferences, access to mental health care providers, and health care cost may all serve as barriers to accessing treatment or contribute to treatment decisions. [24][25][26] The antidepressant treatment patterns analysis found that 68% of patients received antidepressant treatment post-index, which is consistent with a previous study that demonstrated 70% of newly diagnosed patients receive pharmacologic treatment. 14 The present study also found the most common first-line treatment regimen to be monotherapy SSRI, similar to previous studies. [13][14][15] Treatment guidelines recommend starting treatment of MDD with monotherapy SSRIs or SNRIs; our results show that 76% of patients with MDD who initiated antidepressant treatment in our sample started with one of these regimens. 9,10 Patient characteristics, including the presence of co-occurring illnesses and concomitant pharmacotherapy, patient and provider preferences, perceived safety and effectiveness of antidepressants, and health care costs, may be driving medication selection for the remaining sample. 9,24,25 Real-world treatment modalities, health care resource utilization, and costs among commercially insured patients with newly diagnosed major depressive disorder in the United States  The present study identified significant sociodemographic associations with observed treatment modality including age, sex, geographic region, urbanicity of residence, and SES quartile, which is generally consistent with prior literature. It is well established that being female is associated with greater treatment utilization, and our study found that female patients were more likely to use nonpharmacologic vs no treatment than male treatment utilization found in the present study.
A prior study found that those living further from a mental health treatment facility were more likely to receive antidepressant treatment and were less likely to receive psychotherapy. 35 This finding is consistent with the present study, as urbanicity may be serving as a proxy for mental health provider access. Other prior studies have shown inconsistent results related to the role of SES on treatment utilization. [27][28][29][30][31][32] While our study differed from these prior studies in its SES measures (ie, SES in the present study is identified at the neighborhood level as opposed to the individual level), the results in patients. [27][28][29][30][31] In contrast, the finding that increasing age is associated with lower odds of receiving each treatment modality vs no treatment is inconsistent with the literature. Prior studies have consistently observed mental health service utilization to be highest among those who are middle-aged and lowest in younger populations. 27,28,[30][31][32][33] A recent study demonstrated that stigma toward depression has decreased from 2006 to 2018, with millennials (1987-2000 birth cohort) more likely to report lower stigma toward depression than other generations. 34 This growing shift in reduced stigma in younger generations may be one explanation for the association between age and our study provided additional insights and suggest that higher SES might be associated with more treatment utilization. Importantly, our results may have diverged from previous studies, which often assess treatment utilization as binary (any vs none), because the present study offered a more holistic assessment that considered 4 different treatment modalities for both pharmacologic and nonpharmacologic treatments separately. Lastly, distinct study designs and study populations may also have contributed to the differences in outcomes.
In addition to sociodemographic factors, diagnosing provider and location of diagnosis were associated with treatment modality. In the United States, PCPs prescribe most antidepressant medications, whereas many nonphysician clinicians, which include psychologists and LCSWs, are unable to prescribe medications. 36 As such, those diagnosed by these providers may be more likely to participate in psychotherapy, which is within their scope of practice, as opposed to patients diagnosed by PCPs who may have more access to antidepressants. Furthermore, finding a suitable provider able to offer psychotherapy, difficulties obtaining referrals, and unsatisfactory relationships with mental health providers have been found to be barriers to participation in psychotherapy. 26,37 Those who have been diagnosed by a nonphysician clinician have likely overcome that initial barrier leading to further engagement with nonpharmacologic treatment services. Similarly, those diagnosed in outpatient settings may be more likely to engage in treatment as they are already connected with an outpatient provider who can potentially coordinate treatment.
The finding that patients who received combination treatment had the greatest association with improvements in depression severity compared

LIMITATIONS
These findings should be interpreted with consideration of several limitations. First, this study was an exploratory analysis, and the reported associations should not be interpreted as causal effects. In particular, the contemporaneous assessment of treatment modality and MDD severity precludes causal inference. Second, certain characteristics, such as provider preferences, health plan benefit design including the structure of behavioral health coverage, and patient characteristics (eg, individual health-related social needs, family history), were not available, and their effects were not included in our analysis. Third, administrative claims are collected for the purposes of payment and may not reflect true diagnoses and treatment, as coding issues may occur or medications may not be taken as prescribed. Fourth, certain medications (eg, TCAs and bupropion) may have multiple indications, and we were unable to discern for which indication these were prescribed. Fifth, the treatment modality analysis did not consider intensity of treatment, nor did it examine whether patients who received both antidepressant and nonpharmacologic treatment did so concurrently. Sixth, some patients' follow-up time overlapped with the beginning of the COVID-19 pandemic, which may have impacted their access to and utilization of treatments and other health care services. Finally, the study results may not be generalizable to the national level because patients who have commercial health insurance may have different characteristics from those with different types of or no insurance.
with those without treatment is consistent with prior literature showing that psychotherapy in combination with pharmacotherapy provides some additional value compared with pharmacotherapy alone and no treatment. 11,38 To our knowledge, this is the first study to use a claims-based MDD severity measure to assess impact of treatment on improvement in disease severity. Although there are costs associated with providing antidepressant and nonpharmacologic treatment, it is possible that these costs might be offset and even lead to cost savings, as treated patients less frequently require costly high-acuity services, such as inpatient hospitalization and emergency department visits, than those that received no treatment. Indeed, a recent study using realworld data found that patients with MDD who were nonadherent to their medications experienced significantly more inpatient hospitalizations and medical costs than adherent patients. 16 Integration of behavioral health into primary care settings, enabling faster access to psychotherapy for patients, is one possible solution to provide patients with greater access to the MDD treatment modalities needed to improve their symptoms and generate cost savings for the health care system. In this model, a psychologist, LCSW, or other behavioral health provider is a member of the health care team, and both the PCP and in-house behavioral health provider can coordinate to ensure the patient has access to both psychotherapy and pharmacologic treatments without needing to obtain a referral or find an additional provider who offers the other service. 39,40 Integration of behavioral health into primary care has been shown to improve outcomes related to depression as well as improve patient satisfaction and quality of life. 41,42 Additionally, given our finding that patients living in a rural area were